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Development 140 (2): 343-352


Transmembrane/cytoplasmic, rather than catalytic, domains of Mmp14 signal to MAPK activation and mammary branching morphogenesis via binding to integrin β1

Hidetoshi Mori1,*, Alvin T. Lo1, Jamie L. Inman1, Jordi Alcaraz1,2, Cyrus M. Ghajar1, Joni D. Mott1, Celeste M. Nelson1,3, Connie S. Chen1, Hui Zhang1, Jamie L. Bascom1, Motoharu Seiki4, and Mina J. Bissell1,*

1 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
2 Unitat de Biofísica i Bioenginyeria, Universitat de Barcelona, Barcelona 08036, Spain.
3 Chemical and Biological Engineering and Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
4 Institute of Medical Science, University of Tokyo, Tokyo, Japan.

* Authors for correspondence (hmori{at}; mjbissell{at}

Accepted for publication 24 October 2012.

Abstract: Epithelial cell invasion through the extracellular matrix (ECM) is a crucial step in branching morphogenesis. The mechanisms by which the mammary epithelium integrates cues from the ECM with intracellular signaling in order to coordinate invasion through the stroma to make the mammary tree are poorly understood. Because the cell membrane-bound matrix metalloproteinase Mmp14 is known to play a key role in cancer cell invasion, we hypothesized that it could also be centrally involved in integrating signals for mammary epithelial cells (MECs) to navigate the collagen 1 (CL-1)-rich stroma of the mammary gland. Expression studies in nulliparous mice that carry a NLS-lacZ transgene downstream of the Mmp14 promoter revealed that Mmp14 is expressed in MECs at the tips of the branches. Using both mammary organoids and 3D organotypic cultures, we show that MMP activity is necessary for invasion through dense CL-1 (3 mg/ml) gels, but dispensable for MEC branching in sparse CL-1 (1 mg/ml) gels. Surprisingly, however, Mmp14 without its catalytic activity was still necessary for branching. Silencing Mmp14 prevented cell invasion through CL-1 and disrupted branching altogether; it also reduced integrin β1 (Itgb1) levels and attenuated MAPK signaling, disrupting Itgb1-dependent invasion/branching within CL-1 gels. FRET imaging revealed that Mmp14 associates directly with Itgb1. We identified a domain of Mmp14 that is required for modulating the levels of Itgb1, MEC signaling and the rate of invasion within CL-1. These results shed light on hitherto undescribed non-proteolytic activities of Mmp14 that are necessary for the Itgb1-dependent biochemical and mechanical signals that regulate branching in the mammary epithelium.

Key Words: Branching morphogenesisMammary epithelial invasionMmp14Integrin-β1Mouse

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